Daunorubicin during Delayed Intensification Considerably Lowers the Incidence of Infectious Complications but Might Result in Decreased Disease-Free Survival Compared to Adriamycin in Children with Acute Lymphoblastic Leukemia - a Randomized Comparison in Trial Coall 08-09.

Background

The anthracyclines daunorubicin (DNR) and adriamycin (ADR) are are integral components in the frontline treatment of childhood acute lymphoblastic leukemia (ALL). Most reports concerning anthracycline associated toxicity have been focused on cardiotoxicity. Apart from this, severe side effects such as myelosuppression, mucositis and infectious complications have been described for both drugs, but little is known about their differential toxicity profile. To address the question whether DNR is associated with a lower rate of infectious complications compared to ADR we randomized patients in delayed intensification of the CoALL 08-09 trial.

Procedure and results

307 children with newly diagnosed ALL enrolled in trial CoALL08-09 were randomized and received either ADR 30mg/m² (n=153) or DNR 36mg/m² (n=154). Hematologic toxicities as well as stomatitis were more frequent in the ADR group. The analysis of the highest toxicity per patient reveals, that the rate of infectious complications > grade 1 after ADR was significantly higher compared to that after DNR (59% vs 27%, p<0.0001, Fisher's exact test). This holds true for the overall rate of infectious complications between the two arms, taking into account, that high risk patients received two blocks, and therefore could suffer infectious complications at two timepoints. The pattern of infectious pathogens were not different between the two treatment arms. In line with the overall higher rate of infectious complications as described above the frequency of febrile episodes (p<0.0001); (> grade 1: 20% vs 9%, p =0.007) and number of hospitalization days (p<0.0001); (> grade 1: 49% vs 9%, p<0.0001) due to infectious complications after ADR were higher compared to those after DNR. The hematologic toxicity in particular the duration of neutropenia > grade 1 (p<0.0001) and stomatitis >grade 1 (p=0.0003) in the ADR correlated significant with the above described higher rate of infections > grade 1. In the DNR arm a lower grade of stomatitis < 1 (p=0.0004) correlated with a lower grade of an infection. No correlation was found in DNR patients between duration of neutropenia and infectious complication (p= 0.69).

Unexpectedly, we observed an superior outcome for ADR-treated patients with a 90% 4-year DFS (SE 3%) compared to 81% (SE 4%) in the DNR-arm (p=0.11) due to fewer relapses in the ADR arm.

In conclusion, daunorubicin given in delayed intensification is associated with a lower incidence of infectious complications compared to adriamycin, but the 4-year DFS showed a clear trend towards inferior outcome for DNR which outweighs the benefit of lower infection-related morbidities. Hence, within the CoALL frontline protocol for children with ALL ADR will remain the standard treatment element in delayed intensification.